Malignancies of the brain are among the most devastating diseases known. In the US, the prevalence of brain cancer is 360,000, with 15,000 deaths per year. A large percentage of these malignancies are found to be glioblastoma multiforme (GBM), having a very rapid, aggressive, and uncontrolled growth. Very little progress has been made in the treatment of GBM over the past 25 years. Present therapeutic approaches involve surgical excision, chemotherapy, and radiation therapy. The death rate of patients who have been diagnosed as having GBM, however, is 98%. Patients rarely survive for more than one year from diagnosis, often dying within six months. There is on-going research in how to effectively treat GBM.
One experimental approach is “targeted toxin therapy,” in which chemotherapeutics are directly infused into the tumor and the surrounding tissue where the tumor cells begin to infiltrate. This method, while requiring a surgical procedure, has been shown to reduce the debilitating side effects seen with systemic administration. It also reduces concerns regarding medicine crossing the blood brain barrier (BBB), and may achieve very high concentrations of therapeutic agent directly within, and in the vicinity of, the tumor.
Numerous agents for targeted toxin therapy are currently in clinical development. One such targeted toxin is cintredekin besudotox (CB), which is a recombinant protein made up of interleukin-13 and an active toxic protein derived from Pseudomonas exotoxin TP-38. CB binds selectively to the IL-13-overexpressing malignant glioma cells. Other agents being evaluated include standard anti-mitotic chemotherapy agents, transferrin-conjugated toxins, and radioisotope conjugates.
A delivery method for these medicines currently being evaluated is known as “convection-enhanced delivery” (CED), in which the tumor and surrounding tissue are deluged with high volumes of therapeutic agent under positive pressure. This method was designed by NIH researchers to facilitate the infiltration into brain tissue of high molecular weight therapeutic molecules that would not ordinarily diffuse over appreciable distances if simply injected. The parameters for effective CED have been extensively studied and modeled.
Delivery devices to accomplish CED remain under development. Presently, large bore catheters are surgically placed within the malignant mass and an infusion pump is used to drive flow at a rate of approximately 3 mL per hour for extended periods, e.g., up to 4 days. Various catheters have been designed and tested, usually having outer diameters (OD) of 1 mm or greater. Human CED trials are being performed using ventricular shunt tubing (2.1 mm OD) or spinal drains, e.g., 18 gauge, or 1.2 mm in diameter, as delivery cannulas.
These CED delivery methods have a number of shortcomings associated with the size of the delivery catheters. Under high-flow conditions, backflow (or reflux) of the injectable therapeutic occurs in a proximal direction along the outer catheter walls, resulting in a loss of the therapeutic into spaces and regions where it is not intended, and a loss of the pressure required to enable convection of the therapeutic molecules within an interstitial space. These shortcomings are particularly problematic in situations where the tumor is more superficial, as the segment of catheter that is surrounded by brain tissue is reduced. For targets that are deep within the brain, the length of catheter that is surrounded by tissue is increased, and the resistance to back flow is, therefore, also increased. To mitigate this situation, surgery is planned so that the cannula trajectory traverses the longest possible track through the parenchyma to minimize reflux. It has been observed, however, that the larger diameter catheters do not permit precise placement, which is an issue as it is required for more targeted or discrete delivery. Moreover, inserting multiple larger catheters is cumbersome and may limit wide distribution of the therapeutic.
Smaller diameter catheters have been shown to decrease backflow because the amount of backflow decreases as a function of the catheter diameter to the power of four-fifths.
Smaller diameter catheters have less rigidity, therefore, they have required construction in a telescoping, or “step design,” in order to obtain a final catheter diameter of approximately 0.168 mm. Known telescope designs use smaller diameter tubing glued to the end of a rigid stainless steel cannula. The rigid tube, however, is problematic for situations in which it must be left in place, e.g., in the brain, for extended periods of time measured in hours or days. The rigid portion presents a risk to the patient due to, for example, accidental contact and/or movement. Furthermore, while a final diameter of 0.168 mm minimizes reflux, the rate of delivery may be compromised.